Entecavir, the structural formula of which is
is an anti-virally active pharmaceutical compound used in the treatment of hepatitis B infections in humans. It is marketed under the trade name “Baraclude”, as oral tablets and solutions.
Prior art methods of making entecavir involve protection of hydroxyl and hydroxymethyl groups on a cyclopentane starting material with silyl protectant groups, while chemical reaction and derivatization of other groups to form the entecavir molecule are conducted. The silyl protectant groups are removed by hydrolysis in a final or close to final synthetic process step.
There are two significant problems with these prior methods. The first is that the silyl protected intermediates are, in most if not all cases, oils in nature. This renders them difficult to purify. They need the application of chromatographic techniques of purification, which are time-consuming and hence expensive on the commercial scale. The second problem is that the silylated intermediates contain no chromophores capable of absorption of UV light to render them visible in high performance liquid chromatography (HPLC) instrumentation to allow them to be used to track the reactions and determine the purity of the intermediates as they are formed. U.S. Pat. No. 5,206,244 discloses entecavir and analogues thereof, along with methods for their preparation.
It is an object of the present invention to provide a novel synthesis of entecavir and similar compounds, in which these problems are significantly reduced.